Neuronal and retinal tissues are high in phospholipids containing one or two long chain polyunsaturated acyl chains. These studies are directed towards determining a molecular basis for the modulation of G protein-coupled receptor signaling by phospholipids containing polyunsaturated acyl chains, in particular 22:6n-3. Fluorescence Energy Transfer (FRET) was used to determine the degree of lateral domain formation in bilayers containing di16:0 and di22:6 PCs plus cholesterol. Lateral domain formation, which was dependent on the presence of rhodopsin, was detected. Polyunsaturated acyl chains result in the highest level of formation of the active conformation of the G protein-coupled receptor, rhodopsin. The role of lateral domain formation in bilayers containing 22:6n-3 containing lipids is being further investigated. Other experiments indicate that ethanol may disrupt the lateral domains, suggesting a potential mechanism by which ethanol can modulate membrane function. Both acyl chain free volume and curvature stress have been invoked as bilayer properties, which modulate membrane protein function. Experiments are currently being carried out to determine the relationship between these two properties. These studies are important in understanding the role of 22:6n-3 acyl chains in domain formation, the mechanism of alcohol action, and the modulation of membrane protein function